The Effect of Theophylline Ethylene Diamine on Renal Function in Control Subjects and in Patients With Congestive Heart Failure 1

Abstract

The importance of a renal factor in the pathogenesis of peripheral cardiac edema has been emphasized in recent publications ( 1-11 ). The work of Futcher and Schroeder (1) indicated that the renal excretion of salt and water was impaired during cardiac decompensation. Numerous other workers (4-6, 10, 11) reported a reduction in renal blood flow, glomerular filtration rate, and sodium excretion in cases of cardiac failure. These studies resulted in the formulation of two principal hypotheses to explain the retention of sodium and water; namely, (1) low glomerular filtration rate, and (2) more complete reabsorption of sodium and water. More recently, Wesson, Anslow, and Smith (12) have suggested that the low filtration rate delivers a sodium load to the distal tubule which is less than the Tm for sodium and leads to more complete distal tubular reabsorption of sodium.The purpose of this investigation was to study the renal mechanism of sodium and water excretion in cardiac failure by observing the effect of theophylline ethylene diamine (T.E.D.) on filtration rate, effective renal plasma flow, and sodium clearance. Since the results of preliminary experiments suggested that T.E.D. not only increased the tubular load of sodium but also decreased sodium reabsorption, the relationship between tubular load and excretion of sodium could not be determined. However, the simultaneous measurement of filtration rate and sodium clearance during the control periods in patients with cardiac failure afforded an opportunity to study the degree of correlation of these functions under resting conditions. Since the evidence for the mechanism of xanthine diuresis in man is conflicting (4, 11), an extensive study of control subjects was made. MATERIALS AND METHODS SubjectsMale subjects were selected from the wards of the the Baltimore City Hospitals and Infirmary (Home for the Aged).Control subjects were chosen on the basis of a history, physical examination, chest roentgenogram, and urinalysis; cases with hypertension, cardiac and renal diseases were excluded. Although they were selected irrespective of age, most of them were over 50 (range =36-78, mean = 60). All subjects were on a regular diet without salt restriction.The patients in congestive heart failure were selected on the basis of clinical findings characteristic of cardiac decompensation. The

Effect of Meralluride on Solute and Water Excretion in Hydrated Man: Comments on Site of Action*

“…Prompt increases in the rate of salt and water excretion have been described after the intravenous administration of xanthine diuretics in man (23,25). Assuming that theophylline produces an abrupt but transient increase in the quantity of isosmotic fluid escaping proximal tubular reabsorption, CH2O would be expected to rise as a major fraction of this additional solute load is absorbed in the early distal tubule.…”

“…Thereafter, the sustaining infusion was changed to contain one of several "nonspecific solute diuretics," 2 but the rate of infusion was maintained at 20 ml per minute. In four subjects a solution containing 3 (23).…”

Novel therapeutics acting via purine receptors

“…There is evidence that adenosine mediates the tubuloglomerular feedback response [39,40], but it is very unlikely to mediate autoregulation of renal blood flow and glomerular filtration rate [14]. In fact, although the renal hemodynamic effects of theophylline are extremely variable, theophylline actually improves autoregulation in some pathological circumstances [41], and in congestive heart failure, theophylline nearly doubles glomerular filtration rate in humans [42], perhaps because of unusually high levels of endogenously released adenosine. Moreover, as outlined below, there is evidence that endogenously released adenosine explains, at least in part, the renal hemodynamic changes in some experimental animal models of acute renal failure.…”

The Effects of Salt Restriction on the Renal Concentrating Operation in Normal, Hydropenic Man*

“…The enhanced tubular salt and water reabsorption in salt-restricted subjects caused the fraction of urine solute composed of urea to rise 1 Available data suggest that the administration of aminophylline sharply increases salt supply at the ascending limb (19,20). To what extent this change may be a consequence of an increase in GFR or an inhibition of proximal salt absorption is not clear (21). The effect of this agent during a mannitol diuresis would therefore increase the percentage of absorbable solute (salt) presented to the ascending limb, compared to the percentage delivered by a comparable mannitol diuresis alone.…”